Pharmaceutical formulations

ABSTRACT

Disclosed herein are pharmaceutical compositions comprising a plurality of first beads each comprising: a core; a first layer comprising pilocarpine or a pharmaceutically acceptable salt thereof; and a second layer comprising a first polymer. Also disclosed are pharmaceutical compositions comprising a plurality of second beads each comprising: a core; and a first layer comprising tolterodine or a pharmaceutically acceptable salt thereof. Further disclosed are pharmaceutical formulations comprising: a) a plurality of the first beads; b) a plurality of the second beads; or c) a plurality of the first beads and a plurality of the second beads.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/078,881 filed Apr. 1, 2011, now U.S. Pat. No. 9,415,013, which claimspriority to U.S. Provisional Application No. 61/320,202, filed Apr. 1,2010, by Mehdi Paborji, and entitled “PHARMACEUTICAL FORMULATIONS FORTHE TREATMENT OF OVERACTIVE BLADDER,” which applications areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is in the field of pharmaceutical formulations,and in particular formulations comprising pilocarpine or cevimeline,formulations comprising a muscarinic antagonist, and formulationscomprising a combination of pilocarpine or cevimeline and a muscarinicantagonist.

BACKGROUND OF THE DISCLOSURE

Muscarinic receptor antagonists, such as tolterodine, are known for thetreatment of overactive bladder. However, an adverse side effect ofthese treatments is severe dry mouth. This side effect causessignificant patient discomfort and reduces compliance greatly. Previouswork has shown that the combination of tolterodine or oxybutynin withpilocarpine, a muscarinic receptor agonist that increases salivaformation, can significantly reduce the incidents of dry mouth while notaffecting the efficacy of the muscarinic receptor antagonist. See, forexample, U.S. Pat. Nos. 7,666,894, 7,678,821, and 7,781,472, and U.S.Application Publication Nos. 2009/0275629 and 2010/0152263, all of whichare incorporated herein by reference in their entirety.

As discussed in the aforementioned publications, one cannot simply takea muscarinic antagonist and pilocarpine or cevimeline and expect toobtain the desired clinical efficacy. The timing of the administrationof the muscarinic agonist vis-à-vis the administration of the muscarinicantagonist has to be adjusted properly so that the maximum increase insaliva formation due to the administration of the muscarinic agonist isreached at the same time as the maximum dry mouth experienced due to theadministration of the muscarinic antagonist. Taking two tablets at twodifferent times, where the time difference between the twoadministrations has to be exact, is inconvenient, cumbersome, andreduces patient compliance. Therefore, a single pharmaceuticalformulation is needed where the desired time delay and release profileare incorporated.

SUMMARY OF THE INVENTION

Disclosed herein are pharmaceutical compositions comprising a pluralityof first beads each comprising: a core; a first layer comprisingpilocarpine, cevimeline, or a pharmaceutically acceptable salt thereof;and a second layer comprising a first polymer. Also disclosed arepharmaceutical compositions comprising a plurality of second beads eachcomprising: a core; and a first layer comprising a muscarinic antagonistor a pharmaceutically acceptable salt thereof. Further disclosed arepharmaceutical formulations comprising: a) a plurality of the firstbeads; b) a plurality of the second beads; or c) a plurality of thefirst beads and a plurality of the second beads.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Aspects of the present disclosure include pharmaceutical formulationscomprising a muscarinic antagonist in an immediate release formulation.Once ingested by a subject, the muscarinic antagonist in theseformulations begins to release into the gut to be systemically absorbedinto the blood stream. Other aspects of the present disclosure includepharmaceutical formulations comprising pilocarpine or cevimeline, bothof which are muscarinic agonists. The muscarinic agonist of thepharmaceutical formulations is present in a delayed immediate releaseformulation. Once ingested, the muscarinic agonist is not released forsome time. But once the muscarinic agonist begins to be released, it isreleased immediately.

In some embodiments, the muscarinic antagonist of the formulationsdisclosed herein is a compound that is used for the treatment ofoveractive bladder. In certain embodiments, the muscarinic antagonist isselected from the group consisting of tolterodine, 5-hydroxymethyltolterodine, fesoterodine, oxybutynin, solifenacin, darifenacin,trospium, imidafenacin, propiverine, and dicyclomine.

In the context of the present disclosure, “immediate release” or“released immediately” means that at least about 70% of the ingestedactive pharmaceutical ingredient in the dosage form is released from thepharmaceutical formulation within about 30-60 minutes of the ingestionof the dosage form. By “not released” or “delayed released” it is meantthat less than 20% of the ingested active pharmaceutical ingredient inthe dosage form is released from the pharmaceutical formulation by thetime the delay is concluded and the release becomes immediate.

Throughout the present disclosure the term “about” a certain value meansthat a range of value±10%, and preferably a range of value±5%, iscontemplated. Thus, for example, having about 70% of the activepharmaceutical ingredient (API) includes API being present between 63%and 87%, and preferably between 66.5% and 73.5%; or by way of anotherexample, “about 45 minutes” means that the contemplated value is between40.5 minutes and 49.5 minutes, and preferably between 42.75 minutes and47.25 minutes.

Disclosed herein are beads, or multiparticulate systems, comprising amuscarinic agonist, i.e., pilocarpine or cemiveline, and other beadscomprising a muscarinic antagonist. Contemplated within the scope of thepresent disclosure are pharmaceutical compositions comprising muscarinicagonist beads only, muscarinic antagonist beads only, or compositionscomprising both muscarinic agonist and muscarinic antagonist beads. Themuscarinic agonist-only or muscarinic antagonist-only beads can beadministered individually or in combination with beads or otherpharmaceutical formulations comprising other active ingredients.

Muscarinic Agonist Beads

Thus, in one aspect, disclosed herein are pharmaceutical compositionscomprising a plurality of first beads each comprising:

-   -   a core;    -   a first layer comprising a muscarinic agonist, i.e., pilocarpine        or cemiveline, or a pharmaceutically acceptable salt thereof;        and    -   a second layer comprising a first polymer.

In some embodiments, the core comprises a polymer. In certainembodiments, the core polymer is a cellulose polymer. In some of theseembodiments, the cellulose polymer is microcrystalline cellulose. Inother embodiments, the core comprises a sugar. In certain embodiments,the sugar is selected from the group consisting of glucose, sucrose,lactose, mannitol, maltodextrine, xylitol, and sorbitol. In furtherembodiments, the core comprises silicon dioxide.

In some embodiments, the core is obtained commercially. An example ofcommercially available beads to be used as core for the beads disclosedherein includes, but is not limited to, sugar spheres (for example,Paular spheres), Cellets® cores, such as Cellets® 100, Cellets® 200,Cellets® 350, Cellets® 500, Cellets® 700, or Cellets® 1000 (Glatt AirTechniques Inc., Ramsey N.J.). In other embodiments, the core isprepared de novo, for example by preparing a polymer mixture, extrudingthe mixture, and spheronizing the extruded mixture to form spherical orsemi-spherical beads. In some embodiments, the beads are swellable suchthat their exposure to aqueous media causes them to swell and releasethe active ingredient rapidly and efficiently.

In some embodiments, the core comprises between about 10% to about 50%of the total weight of the finally-formulated bead. In some embodiments,the core comprises between about 15% to about 40% of the total weight ofthe finally-formulated bead. In some embodiments, the core comprisesbetween about 20% to about 30% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises about20% of the total weight of the finally-formulated bead. In someembodiments, the core comprises about 25% of the total weight of thefinally-formulated bead.

In some embodiments, a solution of the muscarinic agonist, a free basethereof or a pharmaceutically acceptable salt thereof, is prepared andthen sprayed onto the core and then dried. The act of spraying anddrying causes a layer (the first layer) of the API (i.e., pilocarpine orcevimeline) to form over the bead. In some embodiments, the solutioncomprises a polymer that causes the API to more efficiently adhere tothe core. The amount of the API present in the dosage form can becontrolled by controlling the thickness of the first layer and/or by theconcentration of the solution comprising the API. The thicker the firstlayer, or the more concentrated the API solution, the more API ispresent in the dosage form. Once the first layer is exposed to aqueousmedia, for example gastric or intestinal juice, the pilocarpinecontained therein immediately dissolves into the aqueous medium. Methodsof applying the first layer uniformly onto the core are well-known inthe art.

In some embodiments, the first layer comprises between about 1% to about50% of the total weight of the bead. In some embodiments, the firstlayer comprises between about 2% to about 40% of the total weight of thebead. In some embodiments, the first layer comprises between about 5% toabout 30% of the total weight of the bead. In some embodiments, thefirst layer comprises between about 7% to about 25% of the total weightof the bead. In some embodiments, the first layer comprises betweenabout 8% to about 15% of the total weight of the bead. In someembodiments, the first layer comprises about 8% of the total weight ofthe bead. In some embodiments, the first layer comprises about 10% ofthe total weight of the bead. In some embodiments, the first layercomprises about 12% of the total weight of the bead. In someembodiments, the first layer comprises about 15% of the total weight ofthe bead.

In some embodiments, pilocarpine or cevimeline is present as the freebase. In other embodiments, pilocarpine or cevimeline is present as apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalt” refers to a formulation of a compound that does not abrogate thebiological activity and properties of the compound. Pharmaceutical saltscan be obtained by reacting a compound of the invention with inorganicacids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can be obtained by reacting a compound of the invention withinorganic acids such as tartric acid, oxolic acid, “carbonic acid” toform the bicarbonate or carbonate salt of the compound, acetic acid,formic acid, benzoic acid, and the like. Pharmaceutical salts can alsobe obtained by reacting a compound of the invention with a base to forma salt such as an ammonium salt, an alkali metal salt, such as a sodiumor a potassium salt, an alkaline earth metal salt, such as a calcium ora magnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like. In some embodiments,the pilocarpine is pilocarpine HCl or pilocarpine nitrate.

Once the API (pilocarpine, cevimeline, or a salt thereof) is coated ontothe bead, the bead is coated with a second layer. The second layerdelays the exposure of the first layer to the aqueous media. The secondlayer comprises at least one polymer, the first polymer.

In some embodiments, the first polymer comprises a soluble film-formingpolymer. By “soluble” it is meant that the polymer is soluble in aqueousmedia, which means that at least about 50% of the polymer has dissolvedwithin one hour after exposure to the aqueous media. It is understoodthat some polymers disperse in aqueous solutions. This dispersion is notthe same as dissolving. For a compound or polymer to be soluble, thereneeds to be a concentration of the compound or polymer in the solventhaving solute-solvent interactions, as understood in the chemical arts.

In some embodiments, the first polymer is a sugar or a polysaccharide.In some of these embodiments, the sugar or polysaccharide is selectedfrom the group consisting of cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, maltodextrin, sucrose, modified starch, a saltof alginic acid, soluble gums, and carageenan. In other embodiments, thefirst polymer is polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone(PVPP).

In some embodiments, the soluble-forming polymer is a mixture of two ormore polymers. In some embodiments, the mixture compriseshydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC).

In some embodiments, hydroxypropylmethylcellulose is present in betweenabout 1% to about 50% of the total weight of the bead. In someembodiments, hydroxypropylmethylcellulose is present in between about 2%to about 40% of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 5% to about 30%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 7% to about 25%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 8% to about 15%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in about 8% of the total weightof the bead. In some embodiments, hydroxypropylmethylcellulose ispresent in about 10% of the total weight of the bead. In someembodiments, hydroxypropylmethylcellulose is present in about 12% of thetotal weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in about 15% of the total weightof the bead.

In some embodiments, hydroxypropylcellulose is present in between about1% to about 90% of the total weight of the bead. In some embodiments,hydroxypropylcellulose is present in between about 5% to about 40% ofthe total weight of the bead. In some embodiments,hydroxypropylcellulose is present in between about 10% to about 30% ofthe total weight of the bead. In some embodiments,hydroxypropylcellulose is present in between about 15% to about 25% ofthe total weight of the bead. In some embodiments,hydroxypropylcellulose is present in between about 20% to about 25% ofthe total weight of the bead. In some embodiments,hydroxypropylcellulose is present in about 21.50% of the total weight ofthe bead. In some embodiments, hydroxypropylcellulose is present inabout 22.25% of the total weight of the bead. In some embodiments,hydroxypropylcellulose is present in about 22.75% of the total weight ofthe bead. In some embodiments, hydroxypropylcellulose is present inabout 24.50% of the total weight of the bead.

In some embodiments, the second layer further comprises an insolublefilm-forming polymer. By “insoluble” it is meant that the polymer isinsoluble in aqueous media, which means that at most about 10% of thepolymer has dissolved within one hour after exposure to the aqueousmedia. The presence of the insoluble film-forming polymer in the secondlayer causes greater delay in the exposure of the first layer to theaqueous media. The insoluble film-forming polymer and the solublefilm-forming polymer form a matrix where upon exposure to the aqueousmedia the soluble polymer dissolves leaving pores in a network ofinsoluble polymer through which pores the API in the first layer leachesout into the aqueous media.

In some embodiments, the insoluble film-forming polymer is apolysaccharide. In some of these embodiments, the polysaccharide isselected from the group consisting of ethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, and insoluble gums.In other embodiments, the insoluble film-forming polymer is selectedfrom the group consisting of a polymethacrylate, a polyvinyl alcohol,shellac, and polyvinyl acetate phthalate.

In some embodiments, ethylcellulose is present in between about 1% toabout 90% of the total weight of the bead. In some embodiments,ethylcellulose is present in between about 5% to about 40% of the totalweight of the bead. In some embodiments, ethylcellulose is present inbetween about 10% to about 30% of the total weight of the bead. In someembodiments, ethylcellulose is present in between about 15% to about 25%of the total weight of the bead. In some embodiments, ethylcellulose ispresent in between about 20% to about 25% of the total weight of thebead. In some embodiments, ethylcellulose is present in about 21.50% ofthe total weight of the bead. In some embodiments, ethylcellulose ispresent in about 22.25% of the total weight of the bead. In someembodiments, ethylcellulose is present in about 22.75% of the totalweight of the bead. In some embodiments, ethylcellulose is present inabout 24.50% of the total weight of the bead.

In some embodiments, the second layer comprises hydroxypropylcelluloseand ethylcellulose. In some embodiments, the ratio ofhydroxypropylcellulose to ethylcellulose is between about 5:1 to about1:5 by weight. In some embodiments, the ratio of hydroxypropylcelluloseto ethylcellulose is between about 4:1 to about 1:4 by weight. In someembodiments, the ratio of hydroxypropylcellulose to ethylcellulose isbetween about 3:1 to about 1:3 by weight. In some embodiments, the ratioof hydroxypropylcellulose to ethylcellulose is between about 2:1 toabout 1:2 by weight. In some embodiments, the ratio ofhydroxypropylcellulose to ethylcellulose is about 1:1 by weight.

In some embodiments, the first bead further comprises a de-tackifier ora glidant. In some embodiments, the de-tackifier or glidant is an inertmineral. An inert mineral is a mineral, i.e., an inorganic compound orsalt, that is pharmaceutically acceptable and does not interfere withthe pharmacological action of the therapeutic compound. In someembodiments, the inert mineral is a mineral of magnesium. In otherembodiments, the mineral of magnesium is magnesium silicate. In certainembodiments, the de-tackifier or glidant is selected from the groupconsisting of talc, a monoglyceride, a diglyceride, glycerylmonostearate, calcium stearate, and magnesium stearate.

In some embodiments, the de-tackifier or glidant is present in betweenabout 1% to about 50% of the total weight of the bead. In someembodiments, the de-tackifier or glidant is present in between about 2%to about 40% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in between about 3% to about 20% ofthe total weight of the bead. In some embodiments, the de-tackifier orglidant is present in between about 4% to about 10% of the total weightof the bead. In some embodiments, the de-tackifier or glidant is presentin about 4% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 4.5% of the total weight ofthe bead. In some embodiments, the de-tackifier or glidant is present inabout 5% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 5.5% of the total weight ofthe bead. In some embodiments, the de-tackifier or glidant is present inabout 6% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 6.5% of the total weight ofthe bead.

In some embodiments, the first polymer is, or comprises, a lipidexcipient. The lipid excipient can be selected from the group consistingof glyceryl behenate, glycerol esters of fatty acids, glyceryldibehenate, behenoyl macrogoglycerides, glyceryl distearate, glyceroldistearate, glyceryl palmitostearate, lauroyl macrogoglycerides,stearoyl macrogoglycerides, abitec products, glyceryl mono-oleate,medium chain mono-& diglycerides, glyceryl monocaprylate, glyceryltricaprylate/caprate/stearate, hydrogenated vegetable oil, hydrogenatedcottonseed oil, hydrogenated soybean oil, hydrogenated soybean oil andcastor wax, polyoxyethylene 8 caprylic/capric glycerides,polyoxyethylene 6 caprylic/capric glycerides, polyoxyethylene 32 lauricglycerides, polyoxyethylene 6 prop. Glycol esters, polyoxyethylene 7coconut glycerides, polyoxyethylene 30 coconut glycerides,polyoxyethylene 80 coconut glycerides, polyoxypropylene 15 stearylether, polyoxyethylene 26 glyceryl ether, polyoxyethylene 35 soybeanglycerides, polyoxyethylene 20 sorbitol, polyoxypropylene myristylether, polyoxypropylene 10 cetostearyl ether, palm kernelamidediethanolamide, triglycerol mono-oleate, sasol products, hydrogenatedcoco-glycerides, cetyl palmitate, trimyristin, tripalmitin, tristearin,hydrogenated palm oil, glyceryl monostearate, glyceryl stearate,cetearyl alcohol, cetyl alchohol, capric triglyceride, acetylatedglycerides, glyceryl cocoate, and polyethylene glycol.

In some embodiments, the first bead further comprises a plasticizer. Insome embodiments, the plasticizer is selected from the group consistingof a phthalate-based plasticizer, a trimellitate, an adipate-basedplasticizer, a sebacate-based plasticizer, an organophosphate, amaleate, a sulfonamide, a glycols or polyether, an acetylatedmonoglyceride, and an alkyl citrate.

In some embodiments, the phthalate-based plasticizer is selected fromthe group consisting of bis(2-ethylhexyl) phthalate (DEHP), diisononylphthalate (DINP), bis(n-butyl)phthalate (DnBP, DBP), butyl benzylphthalate (BBzP), diisodecyl phthalate (DIDP), di-n-octyl phthalate (DOPor DnOP), diisooctyl phthalate (DIOP), diethyl phthalate (DEP),diisobutyl phthalate (DIBP), and di-n-hexyl phthalate. In someembodiments, the trimellitate is selected from the group consisting oftrimethyl trimellitate (TMTM), tri-(2-ethylhexyl) trimellitate(TEHTM-MG), tri-(n-octyl,n-decyl) trimellitate (ATM), tri-(heptyl,nonyl)trimellitate (LTM), and n-octyl trimellitate (OTM). In some embodiments,the adipate-based plasticizer is selected from the group consisting ofbis(2-ethylhexyl)adipate (DEHA), dimethyl adipate (DMAD), monomethyladipate (MMAD), and dioctyl adipate (DOA). In some embodiments, thesebacate-based plasticiser is dibutyl sebacate (DBS). In someembodiments, the maleate is dibutyl maleate (DBM) or diisobutyl maleate(DIBM). In some embodiments, the sulfonamide is selected from the groupconsisting of ortho or para N-ethyl toluene sulfonamide (ETSA),N-(2-hydroxypropyl) benzene sulfonamide (HP BSA), and N-(n-butyl)benzene sulfonamide (BBSA-NBBS). In some embodiments, theorganophosphate is tricresyl phosphate (TCP) or tributyl phosphate(TBP). In some embodiments, the glycol or polyether is selected from thegroup consisting of triethylene glycol dihexanoate (3G6, 3GH),tetraethylene glycol diheptanoate (4G7), and polyethylene glycol. Insome embodiments, the alkyl citrate is selected from the groupconsisting of Triethyl citrate (TEC), acetyl triethyl citrate (ATEC),tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate(TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, trihexylo-butyryl citrate), and trimethyl citrate (TMC). In some embodiments,the plasticizer is selected from the group consisting of dibutylsebacate, polyethylene glycol, glycerin, triacetin, diethyl phthalate,propylene glycol, triethyl citrate, mineral oil, an acetylatedmonoglyceride, and oleic acid.

In some embodiments, the plasticizer is present in between about 1% toabout 50% of the total weight of the bead. In some embodiments, theplasticizer is present in between about 2% to about 40% of the totalweight of the bead. In some embodiments, the plasticizer is present inbetween about 3% to about 20% of the total weight of the bead. In someembodiments, the plasticizer is present in between about 4% to about 10%of the total weight of the bead. In some embodiments, the plasticizer ispresent in about 4% of the total weight of the bead. In someembodiments, the plasticizer is present in about 4.5% of the totalweight of the bead. In some embodiments, the plasticizer is present inabout 5% of the total weight of the bead. In some embodiments, theplasticizer is present in about 5.5% of the total weight of the bead. Insome embodiments, the plasticizer is present in about 6% of the totalweight of the bead. In some embodiments, the plasticizer is present inabout 6.5% of the total weight of the bead.

In some embodiments, the weight of the second layer is between about 50%to about 300% of the weight of the bead prior to the application of thesecond layer. In some embodiments, the weight of the second layer isbetween about 75% to about 250% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 75% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 100% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 125% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 150% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 175% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 200% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 225% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 250% of the weight of the bead prior to theapplication of the second layer.

Muscarinic Antagonist Beads

In another aspect, disclosed herein are pharmaceutical compositionscomprising a plurality of second beads each comprising:

-   -   a core; and    -   a first layer comprising a muscarinic antagonist or a        pharmaceutically acceptable salt thereof.

In some embodiments, the muscarinic antagonist is present as the freebase. In other embodiments, the muscarinic antagonist is present as apharmaceutically acceptable salt. Pharmaceutically acceptable salts aredefined above. In some embodiments, the muscarinic antagonist isselected from the group consisting of tolterodine, 5-hydroxymethyltolterodine, fesoterodine, oxybutynin, solifenacin, darifenacin,trospium, imidafenacin, propiverine, and dicyclomine. In someembodiments, the tolterodine is tolterodine tartrate. In otherembodiments, the oxybutynin is oxybutynin chloride.

In some embodiments, the core of the plurality of the second beads iscomprised of the same material as the core of the plurality of the firstbeads, discussed above.

In some embodiments, the core comprises between about 10% to about 90%of the total weight of the finally-formulated bead. In some embodiments,the core comprises between about 25% to about 85% of the total weight ofthe finally-formulated bead. In some embodiments, the core comprisesbetween about 40% to about 80% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises about80% of the total weight of the finally-formulated bead. In someembodiments, the core comprises about 75% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises about85% of the total weight of the finally-formulated bead.

In some embodiments, a solution of the API (i.e., the muscarinicantagonist), or a pharmaceutically acceptable salt thereof, is preparedand then sprayed onto the core and then dried. The act of spraying anddrying causes a layer (the first layer) of the API to form over thebead. In some embodiments, the solution comprises a polymer that causesthe API to more efficiently adhere to the core. The amount of the APIpresent in the dosage form can be controlled by controlling thethickness of the first layer. The thicker the first layer the more APIis present in the dosage form. Once the first layer is exposed toaqueous media, for example gastric or intestinal juice, the tolterodinecontained therein immediately dissolves into the aqueous medium. Methodsof applying the first layer uniformly onto the core are well-known inthe art.

In some embodiments, the first layer comprises between about 1% to about50% of the total weight of the bead. In some embodiments, the firstlayer comprises between about 2% to about 40% of the total weight of thebead. In some embodiments, the first layer comprises between about 4% toabout 25% of the total weight of the bead. In some embodiments, thefirst layer comprises between about 5% to about 15% of the total weightof the bead. In some embodiments, the first layer comprises betweenabout 5.5% to about 10% of the total weight of the bead. In someembodiments, the first layer comprises about 6% of the total weight ofthe bead. In some embodiments, the first layer comprises about 6.5% ofthe total weight of the bead. In some embodiments, the first layercomprises about 7% of the total weight of the bead. In some embodiments,the first layer comprises about 8% of the total weight of the bead.

In some embodiments, the first layer comprises a soluble film-formingpolymer, as defined above.

In some embodiments, hydroxypropylmethylcellulose is present in betweenabout 1% to about 50% of the total weight of the bead. In someembodiments, hydroxypropylmethylcellulose is present in between about 2%to about 40% of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 5% to about 30%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 7% to about 25%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in between about 8% to about 15%of the total weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in about 8% of the total weightof the bead. In some embodiments, hydroxypropylmethylcellulose ispresent in about 10% of the total weight of the bead. In someembodiments, hydroxypropylmethylcellulose is present in about 12% of thetotal weight of the bead. In some embodiments,hydroxypropylmethylcellulose is present in about 15% of the total weightof the bead.

In some embodiments, the second bead further comprises a de-tackifier ora glidant, as defined above. In some embodiments, the de-tackifier orglidant is present in between about 1% to about 50% of the total weightof the bead. In some embodiments, the de-tackifier or glidant is presentin between about 2% to about 40% of the total weight of the bead. Insome embodiments, the de-tackifier or glidant is present in betweenabout 3% to about 20% of the total weight of the bead. In someembodiments, the de-tackifier or glidant is present in between about 4%to about 10% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 3% of the total weight ofthe bead. In some embodiments, the de-tackifier or glidant is present inabout 3.5% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 4% of the total weight ofthe bead. In some embodiments, the de-tackifier or glidant is present inabout 4.5% of the total weight of the bead. In some embodiments, thede-tackifier or glidant is present in about 5% of the total weight ofthe bead. In some embodiments, the de-tackifier or glidant is present inabout 5.5% of the total weight of the bead.

In some embodiments, the first layer further comprises a lipidexcipient. The lipid excipient can be selected from the group consistingof glyceryl behenate, glycerol esters of fatty acids, glyceryldibehenate, behenoyl macrogoglycerides, glyceryl distearate, glyceroldistearate, glyceryl palmitostearate, lauroyl macrogoglycerides,stearoyl macrogoglycerides, abitec products, glyceryl mono-oleate,medium chain mono-& diglycerides, glyceryl monocaprylate, glyceryltricaprylate/caprate/stearate, hydrogenated vegetable oil, hydrogenatedcottonseed oil, hydrogenated soybean oil, hydrogenated soybean oil andcastor wax, polyoxyethylene 8 caprylic/capric glycerides,polyoxyethylene 6 caprylic/capric glycerides, polyoxyethylene 32 lauricglycerides, polyoxyethylene 6 prop. glycol esters, polyoxyethylene 7coconut glycerides, polyoxyethylene 30 coconut glycerides,polyoxyethylene 80 coconut glycerides, polyoxypropylene 15 stearylether, polyoxyethylene 26 glyceryl ether, polyoxyethylene 35 soybeanglycerides, polyoxyethylene 20 sorbitol, polyoxypropylene 3 myristylether, polyoxypropylene 10 cetostearyl ether, palm kernelamidediethanolamide, triglycerol mono-oleate, sasol products, hydrogenatedcoco-glycerides, cetyl palmitate, trimyristin, tripalmitin, tristearin,hydrogenated palm oil, glyceryl monostearate, glyceryl stearate,cetearyl alcohol, cetyl alchohol, capric triglyceride, acetylatedglycerides, glyceryl cocoate, and polyethylene glycol.

In some embodiments, the second bead further comprises a plasticizer, asdefined above. In some embodiments, the plasticizer is polyethyleneglycol. In certain embodiments, the polyethylene glycol is PEG 400.

In some embodiments, the plasticizer is present in between about 0.1% toabout 50% of the total weight of the bead. In some embodiments, theplasticizer is present in between about 0.1% to about 40% of the totalweight of the bead. In some embodiments, the plasticizer is present inbetween about 0.1% to about 5% of the total weight of the bead. In someembodiments, the plasticizer is present in between about 0.2% to about2% of the total weight of the bead. In some embodiments, the plasticizeris present in about 0.1% of the total weight of the bead. In someembodiments, the plasticizer is present in about 0.15% of the totalweight of the bead. In some embodiments, the plasticizer is present inabout 0.2% of the total weight of the bead. In some embodiments, theplasticizer is present in about 0.25% of the total weight of the bead.In some embodiments, the plasticizer is present in about 0.3% of thetotal weight of the bead. In some embodiments, the plasticizer ispresent in about 0.35% of the total weight of the bead. In someembodiments, the plasticizer is present in about 0.4% of the totalweight of the bead.

In some embodiments, the second beads further comprise a second layer.In some embodiments, the second layer comprises ingredients similar tothe first layer, discussed above, except that the second layer does nothave any API. In some embodiments, the first layer and the second layerhave identical set of ingredients, whereas in other embodiments, thefirst and second layers have different combination of ingredients.

Pharmaceutical Formulations

In another aspect, disclosed herein are pharmaceutical formulationscomprising one of the following combinations of the above beads: a) aplurality of the first beads; b) a plurality of the second beads; or c)a plurality of the first beads and a plurality of the second beads.

The disclosed pharmaceutical formulations contain sufficient number ofbeads to provide a single administrable dose to a subject. In someembodiments, a single administrative dose for the muscarinic agonist isbetween 0.5-50 mg. In certain embodiments, a single administrable doseof pilocarpine is selected from the group consisting of 3 mg, 4 mg, 5mg, 6 mg, 10 mg, 11 mg, and 12 mg. In other embodiments, a singleadministrable dose of cevimeline is selected from the group consistingof 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, and 60 mg. Incertain embodiments, a single administrable dose for the muscarinicantagonist is between 0.1-100 mg. In certain embodiments, a singleadministrative dose is selected from the group consisting of 0.1 mg, 0.2mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8mg, 10 mg, 12 mg, 15 mg, 30 mg, and 60 mg.

In some embodiments, the pharmaceutical formulations are in the form ofcapsules. The capsules may include push-fit capsules made of gelatin,push-fit capsules, for example those made ofhydroxypropylmethylcellulose, banded push-fit capsules, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol.

In some embodiments, the pharmaceutical formulations are in the form ofdose sipping straws. In some embodiments, the beads are filled into astraw and a patient then drinks liquid through the straw, and throughthe process of drinking, the liquid pulled through the straw brings thebeads into the mouth along with the liquid.

In some embodiments, the pharmaceutical formulations are in the form ofdry sachets. In some embodiments, the beads are sprinkled onto food ormixed into a drink from dry sachet, and taken orally. For the dosage tobe effective, the disclosed beads are filled into a sachet pouch, alongwith additional excipients needed to form a readily dispersiblesuspension. When the pouch is opened and the contents are poured overfood or into a drink, the beads and additional excipients are mixed withthe food or the drink, and form a palatable dispersion that is ingestedby the subject. Excipients, such as salivants and glidants, are addedfor the contents to be easily swallowed with a minimum of chewing sothat the coatings are not broken in the mouth.

In some embodiments, the pharmaceutical formulations are in the form ofready-to-use sachets. In some embodiments, the beads are premixed withan edible, high viscosity food substance (for example, yogurt, or energygel), and the entire contents of the package is taken orally.Excipients, such as salivants and glidants, are added for the contentsto be easily swallowed with a minimum of chewing so that the coatingsare not broken in the mouth.

In some embodiments, the pharmaceutical formulations are in the form ofsuspensions. In some embodiments, the suspensions comprise ingredientssuch as glycerin, microcrystalline cellulose, carboxymethyl cellulosesodium, sorbitol solution, xanthan gum, and the like, and variouscolorings and flavorings to make the suspension palatable for pediatricor geriatric use.

In some embodiments, the first beads disclosed above, having pilocarpineor a pharmaceutically acceptable salt thereof, and the first and secondlayers, are coated with a third layer comprising tolterodine, or apharmaceutically acceptable salt thereof. The third layer is the sameas, or similar to, the first layer of the second beads discussed above.In certain embodiments, the tolterodine-coated first bead is furthercoated with a fourth layer, which is the same as, or similar to, thesecond layer of the second beads discussed above.

EXAMPLES Example 1: Materials Used in the Bead Manufacturing Process

The raw materials listed in Table 1 were used in the production of thepilocarpine and tolterodine beads.

TABLE 1 Components Used for Bead Production Generic Name Trade NameSupplier Pilocarpine Hydrochloride Pilocarpine HCl Boehringer IngelheimTolterodine Tartrate Tolterodine tartrate Medichem EthylcelluloseEthylcellulose N10 Hercules Ethylcellulose Ethylcellulose N7 HerculesHydroxypropyl Pharmacoat 606 Shin Etsu Methylcellulose HydroxypropylCellulose Klucel EF Hercules Polyethylene Glycol 400 Carbowax 400 DowDibutyl Sebacate Dibutyl Sebacate Vertellus Talc Luzenac Talc Mineralsand Pigments Dehydrated Alcohol, 200 Ethanol Spectrum proofMicrocrystalline Cellulose Cellets 700 Glatt Beads GMS EmulsionPlasacryl Emerson Microcrystalline Cellulose Avicel PH 101 FMC MilledLactose Pharmatose 200M DMV Croscarmellose Sodium Ac-Di-Sol FMCCrospovidone Polyplasdone XL-10 ISP Gelatin Capsules Conisnaps, size 2Capsugel Sterile water for Irrigation Water Hospira Deionized waterDeionized water N/A

The equipment listed in Table 2 was used for the preparation of thebeads.

TABLE 2 Equipment Used for Bead Production Equipment ManufacturerLocation FLM-1 fluid bed Vector Corporation Marion, IA FLM-3 fluid bedVector Corporation Marion, IA DG-L1 Extruder LCI Charlotte, NC QJ-230Spheronizer LCI Charlotte, NC Blend Master V-blender Patterson KellyEast Stroudsburg, PA In Cap Automatic Encapsulator Dott. Bonapace &Milan, Italy C. ProFill 100 Manual Encapsulator Capsugel Greenwood, SCPortable Dehumidifier DRI-EAZ Burlington, WA

Example 2: Dissolution Rate Determination

This method describes the procedure for the determination of thedissolution rate of the pilocarpine HCl and tolterodine tartratecombination formulations by using a reverse-phase, gradient,high-pressure liquid chromatography (HPLC) method, using techniqueswell-known in the art.

Stock solutions of pilocarpine HCl and tolterodine tartrate wereprepared as working standards. Beads containing pilocarpine HCl andtolterodine tartrate are separately mixed with a fixed volume of 0.1 NHCl. At fixed time points after the mixing has begun, aliquots of thedissolution mixtures are injected into HPLC followed by several aliquotsof the working standards. The amounts of released (dissolved)tolterodine and pilocarpine entities of formulations were calculatedusing the corresponding peak areas of tolterodine and pilocarpine.

A USP 2 Paddles method with the following conditions was employed todetermine dissolution of various formulations.

-   -   Dissolution media: 0.1 N HCl    -   Agitation Rate: 50 RPM    -   Vessel Temp: 37° C.±0.5° C.    -   Sample Volume: 1.0 mL    -   Disso Volume: 500 mL

Example 3: Bead Formation

Beads were produced by drug layering microcrystalline cellulose beadswith aqueous, cellulosic coating systems containing pilocarpine HCl ortolterodine tartrate. The beads were formulated into single dose units.The coating formulations are displayed in Tables 3 and 4 below:

TABLE 3 Sample A: Tolterodine Tartrate Drug Layering: Component mg/unit% w/w Microcrystalline Cellulose Beads 25.0 79.4 Tolterodine Tartrate2.0 6.3 HPMC 3.1 9.8 Talc 1.1 3.5 PEG 400 0.3 1.0 Total 31.5 100.0

TABLE 4 Sample B: Pilocarpine HCl drug layering: Component mg/unit % w/wMicrocrystalline Cellulose Beads 27.5 50.0 Pilocarpine HCl 11.0 20.0HPMC 11.0 20.0 Talc 5.5 10.0 Total 55.0 100.0

Both coating solutions were applied to the Microcrystalline Cellulose(MCC) Pellets using a Vector FLM-1 fluid bed with a Wurster coatingconfiguration. Beads were hand-filled into size 2 gelatin capsules andtested for dissolution using the procedure of Example 2. The dissolutiondata of the drug layered beads are shown in Tables 5 and 6:

TABLE 5 Sample A: Tolterodine Tartrate Release Data % Dissolved at TimePoint (min) Vessel # 0 5 12 20 30 45 60 V1 0 77 109 113 113 114 114 V2 071 100 104 106 108 108 V3 0 45 96 106 111 113 113 V4 0 43 100 109 112113 113 V5 0 61 100 105 108 110 110 V6 0 43 92 107 111 113 113 Mean 0 5699 107 110 111 112 SD 0 15.1 5.7 3.2 2.5 2.4 2.3 % RSD 0.00% 26.73%5.74% 2.96% 2.29% 2.17% 2.04%

TABLE 6 Sample B: Pilocarpine HCl Release Data % Dissolved at Time Point(min) Vessel # 0 10 20 30 45 60 V1 0 100 104 105 105 105 V2 0 99 106 106106 106 V3 0 102 106 107 106 106 V4 0 101 106 106 107 107 V5 0 105 108108 108 108 V6 0 93 109 109 109 109 Mean 0 100 107 107 107 107 SD 0 4.01.8 1.5 1.5 1.5 % RSD 4.0% 1.7% 1.4% 1.4% 1.4%

Both types of drug layered beads were top-coated. The tolterodine beadswere coated with a thin, immediate release HPMC based coating system toensure no tolterodine tartrate was lost from erosion. The topcoat forthe pilocarpine HCl beads was developed in rounds 2-5 of development.

Example 4: Bead Formation

The development in this example focused on the use of several types andgrades of cellulosic polymers in order to form a semi-permeable barrierthat would delay release. All coatings applied were at relatively lowweight gains, no higher than 50%. It was determined that the applicationof high weight gains produced the desired delayed release profile. Theformulations and release profiles are summarized in Table 7 below:

TABLE 7 Formulations Reference Film Component % w/w A HPMC 606 40 EC N1040 Talc 20 C HPC EF 24 EC N7 56 Talc 20 D HPC EF 32 EC N7 48 Talc 20 EHPC EF 24 EC N10 56 Talc 20 F HPC EF 87 Plasacryl 13 G EC N7 90.9Dibutyl Sebacate 9.1 H EC N10 90.9 Dibutyl Sebacate 9.1

The dissolution data of the beads of Samples F and G, obtained using theprocedure of Example 2, are shown in Tables 8 and 9:

TABLE 8 Sample F Dissolution Data % Dissolved at Time Point (min) Vessel# 0 10 20 30 45 60 75 90 120 Infinity V1 0 9 48 71 84 89 96 99 101 101V2 0 9 50 77 92 95 96 97 97 97 Mean 0 9 49 74 88 92 96 98 99 99 SD 0 0.01.4 4.2 5.7 4.2 0.0 1.4 2.8 2.8 % RSD 0.0% 2.9% 5.7% 6.4% 4.6% 0.0% 1.4%2.9% 2.9%

TABLE 9 Sample G Dissolution Data % Dissolved at Time Point (min) Vessel# 0 10 20 30 45 60 75 90 120 Infinity V1 (1%)* 0 53 73 84 92 96 99 100102 102 V2 (1%)* 0 55 73 84 93 99 102 103 104 104 Mean 0 54 73 84 93 98101 102 103 103 SD 0 1.4 0.0 0.0 0.7 2.1 2.1 2.1 1.4 1.4 % RSD 2.6% 0.0%0.0% 0.8% 2.2% 2.1% 2.1% 1.4% 1.4% V3 (4%)* 0 2 8 21 42 59 71 81 92 96V4 (4%)* 0 2 9 22 43 59 71 82 91 95 Mean 0 2 9 22 43 59 71 82 92 96 SD 00.0 0.7 0.7 0.7 0.0 0.0 0.7 0.7 0.7 % RSD 0.0% 8.3% 3.3% 1.7% 0.0% 0.0%0.9% 0.8% 0.7% V5 (8%)* 0 1 4 7 14 22 32 41 57 65 V6 (8%)* 0 1 3 5 11 1928 36 52 61 Mean 0 1 4 6 13 21 30 39 55 63 SD 0 0.0 0.7 1.4 2.1 2.1 2.83.5 3.5 2.8 % RSD 0.0% 20.2% 23.6% 17.0% 10.3% 9.4% 9.2% 6.5% 4.5% *Thepercentages refer to different film thicknesses.

Example 5: Bead Formation

In this example, swellable beads containing pilocarpine HCl wereproduced. First, placebo beads were produced in order to compare twocommon super-disintegrants. The criterion for super-disintegrantselection was volume increase as the beads were placed in 0.1 N HCl. Theformulations and results are below in Table 9:

TABLE 9 Placebo bead formulations Experiment Reference Bead Component %w/w I Microcrystalline Cellulose 45 Lactose 45 Croscarmellose Sodium 10J Microcrystalline Cellulose 45 Lactose 45 Crospovidone 10

Two swellable pilocarpine HCl bead formulations were produced, withdiffering quantities of pilocarpine. These beads were then each coatedwith the same ethylcellulose based coating system and tested fordissolution. The formulations and results are set forth below in Table10.

TABLE 10 Pilocarpine HCl swellable bead formulations ExperimentReference Component % w/w K bead Microcrystalline Cellulose 40.6 Lactose40.6 Croscarmellose Sodium 8.8 Pilocarpine HCl 10.0 L beadMicrocrystalline Cellulose 43.1 Lactose 43.1 Crospovidone 8.8Pilocarpine HCl 5.0 K and L coating Ethylcellulose N7 90.9 formulationDibutyl Sebacate 9.1

As shown in the dissolution data in Table 11, the formulations had thedesired delayed release, obtained using the procedure of Example 2.

TABLE 11 Samples K and L Dissolution Data % Dissolved at Time Point(min) Vessel # 0 10 20 30 45 60 Infinity K-1 (4%) 0 1 4 17 44 61 72 K-2(8%) 0 0 0 1 3 7 12 K-3 (12%) 0 0 0 0 1 2 3 L-1 (4%) 0 1 4 12 29 42 53L-2 (8%) 0 0 0 1 2 5 10 L-3 (12%) 0 0 0 1 1 3 4

Example 6: Bead Formation

This example focused on coating drug-layered microcrystalline cellulosecores with cellulosic polymers to high weight gains (up to 200%). Thefirst coating formulation consisted of a soluble polymer,hydroxypropylcellulose (HPC), which forms a hydrogel that delaysrelease. The second formulation consisted of a 1:1 ratio of HPC andethylcellulose. The thickness of both types of films directly correlatedto the delay in release of pilocarpine HCl. The formulations for eachprototype are shown below in Table 12.

TABLE 12 High weight gain cellulosic coatings Experiment Reference FilmComponent % w/w M, N HPC EF 45.45 EC N10 45.45 Talc 9.10 O HPC EF 87Plasacryl 13

Beads having the following weight gains were produced: 75%, 100%, 125%,150%, 175%, and 200%. This set of beads exhibited a wide range of lagtimes, followed by immediate release. The delay in release is controlledby the thickness of the film. The dissolution data, obtained using theprocedure of Example 2, are shown in Tables 13 and 14.

TABLE 13 Samples M and N Dissolution Data % Dissolved at Time Point(min) Sample Description 0 5 12 20 30 45 60 75 Infinity M-1 (75%) 0 0 012 76 94 96 98 98 M-2 (100%) 0 0 0 1 33 90 95 96 96 N-1 (125%) 0 0 0 0 274 98 100 100 N-2 (150%) 0 0 1 0 0 27 89 98 99 N-3 (175%) 0 0 0 0 0 6 6896 99 N-4 (200%) 0 0 0 1 0 1 28 83 93

TABLE 14 Sample O Dissolution Data % Dissolved at Time Point (min)Sample Description 0 5 12 20 30 45 60 75 Infinity O-1 (80%) 0 0 5 25 4867 76 80 82 O-2 (100%) 0 0 2 15 40 62 72 78 83 O-3 (120%) 0 0 0 3 23 5370 79 86 O-4 (140%) 0 0 1 3 15 46 65 76 83 O-5 (150%) 0 0 0 2 14 48 6676 83

Example 7: Cevimeline Bead Formation

Cevimeline beads are produced in substantially the same manner aspilocarpine beads, as described above, except that cevimeline is usedinstead of pilocarpine.

Example 8: Muscarinic Antagonist Bead Formation

Beads containing a muscarinic antagonist selected from the groupconsisting of the muscarinic antagonist is selected from the groupconsisting of 5-hydroxymethyl tolterodine, fesoterodine, oxybutynin,solifenacin, darifenacin, trospium, imidafenacin, propiverine, anddicyclomine are prepared in substantially the same manner as tolterodinebeads, as described above, except that the specific muscarinicantagonist is used instead of tolterodine.

What is claimed is:
 1. A pharmaceutical composition comprising aplurality of first beads each comprising: a core; a first layercomprising a muscarinic agonist or a pharmaceutically acceptable saltthereof; and a second layer comprising hydroxypropylcellulose andethylcellulose in a weight ratio of about 1:1, wherein the plurality ofbeads are each configured to release 70% or more of the muscarinicagonist or pharmaceutically acceptable salt thereof during a period offrom 20 minutes to 50 minutes following immersion in 0.1 N HCl at 37° C.2. The pharmaceutical composition of claim 1, wherein the muscarinicagonist or pharmaceutically acceptable salt thereof is pilocarpine or apharmaceutically acceptable salt thereof.
 3. The pharmaceuticalcomposition of claim 1, wherein the core comprises a cellulose polymer,silicon dioxide, glucose, sucrose, lactose, mannitol, xylitol, orsorbitol, or a combination thereof.
 4. The pharmaceutical composition ofclaim 1, wherein the core comprises between about 10% to about 50% ofthe total weight of the finally-formulated bead.
 5. The pharmaceuticalcomposition of claim 1, wherein the first layer comprises between about1% to about 50% of the total weight of the bead.
 6. The pharmaceuticalcomposition of claim 1, wherein each bead further comprises ade-tackifier or a glidant.
 7. The pharmaceutical composition of claim 6,wherein the glidant is selected from the group consisting of talc,glyceryl, monostearate, calcium stearate, and magnesium stearate.
 8. Thepharmaceutical composition of claim 1, wherein each bead furthercomprises a plasticizer.
 9. The pharmaceutical composition of claim 8,wherein the plasticizer is selected from the group consisting of aphthalate, a trimellitate, an adipate, a sebacate, an organophosphate, amaleate, a sulfonamide, a glycols or polyether, an acetylatedmonoglyceride, and an alkyl citrate.
 10. The pharmaceutical compositionof claim 1, wherein the first layer further comprises a lipid excipient.11. The pharmaceutical composition of claim 10, wherein the lipidexcipient is selected from the group consisting of glyceryl behenate,glycerol esters of fatty acids, glyceryl dibehenate, behenoylmacrogoglycerides, glyceryl distearate, glycerol distearate, glycerylpalmitostearate, lauroyl macrogoglycerides, stearoyl macrogoglycerides,abitec products, glyceryl mono-oleate, medium chain mono& diglycerides,glyceryl monocaprylate, glyceryl tricaprylate/caprate/stearate,hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenatedsoybean oil, hydrogenated soybean oil and castor wax, polyoxyethylene 8caprylic/capric glycerides, polyoxyethylene 6 caprylic/capricglycerides, polyoxyethylene 32 lauric glycerides, polyoxyethylene 6prop. glycol esters, polyoxyethylene 7 coconut glycerides,polyoxyethylene 30 coconut glycerides, polyoxyethylene 80 coconutglycerides, polyoxypropylene 15 stearyl ether, polyoxyethylene 26glyceryl ether, polyoxyethylene 35 soybean glycerides, polyoxyethylene20 sorbitol, polyoxypropylene 3 myristyl ether, polyoxypropylene 10cetostearyl ether, palm kernelamide diethanolamide, triglycerolmono-oleate, sasol products, hydrogenated coco-glycerides, cetylpalmitate, trimyristin, tripalmitin, tristearin, hydrogenated palm oil,glyceryl monostearate, glyceryl stearate, cetearyl alcohol, cetylalchohol, capric triglyceride, acetylated glycerides, glyceryl cocoate,and polyethylene glycol.
 12. A pharmaceutical composition comprising: afirst set of beads, each bead of the first set of beads comprising: acore; a first layer comprising a muscarinic agonist or apharmaceutically acceptable salt thereof; and a second layer comprisinghydroxypropylcellulose and ethylcellulose in a weight ratio of about1:1, wherein the beads of the first set are each configured to release70% or more of the muscarinic agonist or pharmaceutically acceptablesalt thereof during a period of from 20 minutes to 50 minutes followingimmersion in 0.1 N HCl at 37° C.; and a second set of beads differentfrom the first set of beads, the second set of beads comprising amuscarinic antagonist or a pharmaceutically acceptable salt thereof. 13.The pharmaceutical composition of claim 12, wherein the muscarinicantagonist is selected from the group consisting of tolterodine,5-hydroxymethyl tolterodine, fesoterodine, oxybutynin, solifenacin,darifenacin, trospium, imidafenacin, propiverine, and dicyclomine. 14.The pharmaceutical composition of claim 13, wherein the muscarinicantagonist is oxybutynin or a pharmaceutically acceptable salt thereof.15. The pharmaceutical composition of claim 12, wherein the muscarinicagonist is pilocarpine or a pharmaceutically acceptable salt thereof.16. The pharmaceutical composition of claim 12, wherein thepharmaceutical composition comprises 0.5-50 mg of the muscarinicagonist.
 17. The pharmaceutical composition of claim 12, wherein thepharmaceutical composition comprises 0.1-100 mg of the muscarinicantagonist.
 18. The pharmaceutical composition of claim 1, wherein, inaddition to the plurality of first beads, the pharmaceutical compositioncomprises a muscarinic antagonist or a pharmaceutically acceptable saltthereof.
 19. The pharmaceutical composition of claim 18, wherein, inaddition to the plurality of first beads, the pharmaceutical compositioncomprises oxybutynin or a pharmaceutically acceptable salt thereof.